Much evidence points to tau- and amyloid-related cellular alterations as major contributing factors to the pathogenesis of Alzheimer's disease (AD). Although numerous studies of neuronal pathology have been carried out in the human brain, they have rarely been performed in a way to assess the effects of the progression of pathological lesions on the morphologic integrity of identified neuronal subpopulations and have generally not been quantitative. This project will investigate the spatial and temporal linkage between abnormally phosphorylated tau and amyloid accumulation, and dendritic atrophy and spine loss in different subtypes of neocortical pyramidal cells characterized by neurochemical and morphologic features. Such putative interactions will be investigated in four groups of human postmortem specimens: 1) neurologically normal elderly cases, 2) cases with mild cognitive impairment and early AD, 3) cases with moderate dementia, and 4) severe AD cases, as well as in a mouse model that expresses only the human tau gene. The early AD cases will emerge as a particularly interesting group of brains as they will permit us to pinpoint the earliest changes in dendritic function in neocortical neurons that have a known risk of enhanced vulnerability to the degenerative process of AD. Based on stereologic analyses from our laboratory, we expect that a small subgroup of large neocortical neurons enriched in nonphosphorylated neurofilaments are the first to contain dendritic lesions that precede the stage at which neurofibrillary tangles (NFT) are forming and dementia becomes evident. These analyses will focus on Brodmann's area 9 in the prefrontal cortex. Area 9 is a severely and early affected neocortical field in AD, which we have extensively characterized in terms of selective neuronal vulnerability. In this project we will expand the regional stereologic assessments of identified neuronal subgroups gathered during the previous funding period by analyzing cellular alterations and their relationships to deposition of amyloid and age-related neuronal pathology at the level of individual neuron morphology. The analyses in mice will permit us to follow the dynamic changes in live animals, obtain very high resolution imaging datasets prior to sectioning these specimens for detailed morphologic analyses, and provide quantitative analyses of neurons potentially at risk of degeneration with a much higher level of resolution than would be achievable in human postmortem materials. Altogether this project will provide a quantitative assessment, in AD cases of different severity, of the relative contribution of age-related neuritic pathology, early stages of amyloid processing, and senile plaques, to the progressive demise of selectively vulnerable neuronal subsets subserving cortical circuits critical for memory and cognition.